IL-33 in T Cell Differentiation, Function, and Immune Homeostasis

Recent studies have highlighted a role for the alarmin interleukin (IL)-33 in CD4+ and CD8+ T cell activation and function, and have also revealed important distinctions. The IL-33 receptor ST2 is constitutively and abundantly expressed on T-helper-2 (Th2) and GATA-3+ regulatory T cells in a GATA-3- and STAT5-dependent manner. Upon activation, Th1 and cytotoxic T cells express ST2 transiently, driven by T-bet and/or STAT4. We review these findings here, and critically examine evidence indicating that IL-33 enhances the differentiation and functionality of various T cell subsets through positive feedback loops involving lineage-specifying transcription factors. In this context, we discuss how quantitative and qualitative differences in ST2 expression between effector and GATA-3+ regulatory T cells may contribute to immune homeostasis, and outline important areas of future inquiry.

TrendsIL-33 was initially associated with type 2 and innate immunity. However, recent studies in IL-33 signaling-deficient mice show that it is crucial for protective antiviral T cell responses. Activated T helper 1 (Th1) and CD8+ T cells express the IL-33 receptor ST2 transiently, albeit in lower amounts than Th2 cells.GATA-3+ regulatory T cells in the intestine express ST2 in a constitutive manner and in high amounts, as do Th2 cells.Several studies reveal that IL-33 is a broadly active, soluble costimulator of T cells. It promotes the expansion and functional differentiation of various effector T cell subsets as well as GATA-3+ regulatory T cells.At the molecular level, IL-33 signaling directly or indirectly boosts the expression of the lineage-specifying transcription factors T-bet, GATA-3, and Foxp3. In turn, T-bet and GATA-3 control and enhance ST2 expression, thus forming a positive feedback loop.